SUMMARYThe present study aimed to investigate the hypothesis that the function of the Na,Caexchanger (NCX) is of higher importance for contractility and Ca
2+-homeostasis in left ventricle from terminally failing than from nonfailing human hearts.The effect of decreasing extracellular [Na] e (140 to 25 mmol/L) on force of contraction in isolated left ventricular papillary muscle strips was studied as a reflection of NCX function in multicellular preparations (terminally failing, DCM, dilated cardiomyopathy, NYHA IV, n = 13; nonfailing, NF, donor hearts, n = 10). Decreasing [Na] e has previously been shown to increase contractility in vitro secondary to a decreased Ca 2+ -extrusion by the NCX. In addition, the NCX activity was measured as Na + -dependent 45 Ca 2+ -uptake into isolated myocardial vesicles as a function of time and Ca 2+ -concentration (DCM n = 8, NF n = 8). Decreasing [Na] e enhanced the contractility of papillary muscle strips in both DCM and NF, but the contractility of DCM was increased at smaller reductions of [Na] e than NF. The NCX activity in isolated myocardial vesicles was unchanged as a function of time (T 1/2 : DCM 2.4 ± 0.3 s versus NF 2.5 ± 0.3 s) and as a function of Ca These results demonstrate a higher sensitivity of the failing human myocardium towards Na,Ca-exchanger mediated positive inotropic effects, suggesting a higher significance of the Na,Ca-exchanger for the extrusion of Ca 2+ -ions in intact failing versus nonfailing human myocardium. Since the activity and the Ca 2+ -affinity of the Na,Caexchanger in isolated vesicles was unchanged, we propose that alterations in Ca 2+ -and Na + -homeostasis (due to impaired function of the sarcoplasmic reticulum and the Na + , K + -ATPase) or the prolonged action potential are the reason for this observation. (Int Heart J 2007; 48: 755-766)